DESCRIPTION (applicant's abstract): The hypothesis driving this project is that peptidases in the immune system are important in modulating both local opioid peptide concentrations and the spectrum of active opioid peptides. Regulated expression of peptidase activity is a powerful mechanism having potential to terminate or alter receptor recognition, signal transduction, and physiological responses of immune cells to exogenous opiate peptides. Opioid peptides are reported to serve as regulatory signals between the neuroendocrine and immune systems as well as among immune system cells. Opioid peptides (i.e., enkephalins and endorphins) affect a number of immune system functions in vitro (e.g., antibody production, cell proliferation, cytotoxicity, lymphokine production, and chemotaxis). Some immunocompetent cell types synthesize and release enkephalins and endorphins in response to inflammatory stimuli. Opioids have been reported to modulate severely compromised immune systems (e.g., acquired immunodeficiency syndrome and cancer). Our recent studies on beta-endorphin (B-EP) metabolism suggest that an intracellular peptidase referred to as insulin degrading enzyme (IDE), also known as beta-endorphin generating enzyme (EpGE), is responsible for the metabolism of this opioid peptide in immune cells. The proposed studies focus on the regulation of expression and function of this IDE/(EpGE as it is related to B-EP metabolism and function in immune cells. A unique mechanism is suggested by these studies involving the uptake of B-EP by stimulated macrophages, the conversion of the internalized B-EP to active metabolites by IDE, and the secretion of the peptide products. Based on these novel observations three aims are proposed: 1) To determine how the expression of IDE/EpGE is regulated during the activation of T cells and maturation / stimulation of macrophages. 2) To elucidate the mechanisms involved in the uptake of B-EP and the secretion of B-EP and other B-EP metabolites by macrophages. 3) To identify the B-EP transporter/receptor.